The symptoms of human allergic disease or more properly the allergic syndrome, are brought about through the release into the organism of vasoactive amines, notably histamine. The histamine is normally stored in special cells known as mast cells and basophil leucocytes distributed throughout the organism. The mast cells are dispersed throughout human tissue structures, while the basophils circulate with the blood in the body, i.e., within the vascular system.
The above-noted cells manufacture and store histamine within their internal structures, and the histamine remains therein unless a specialized sequence of events occur to trigger the release of histamine from within the cell structures into the surrounding tissues and vascular system.
More specifically, histamine will be released in response to the presence of specific antigens (allergens) that gain entrance into the organism or may be released by the organism in response to some traumatic occurrence. However, the usual release of histamine from the mast cells or basophils is triggered by a necessary sequence of chemical and immunological events taking place on and in the mast cell and basophil structures.
Specifically, the allergen-mast cell (basophil) interaction is mediated by a group of proteins known as immunoglobulin E (IgE) that are manufactured within the body. The IgE manufactured by the human organism is a complex arrangement of polypeptide chains, each molecule of which may have certain variations in the sequence of amino acids in the polypeptide chain, but all of which in essence may be characterized as having a "Y" like structure, wherein the "tail" (actually the base of the "Y") (Fc) polypeptide portion or fragment contains a fixed sequence or "constant region" of peptides along the chain. The "heads" (which are equivalent to the upper arms of the "Y" structure) may have regions wherein the polypeptide chain varies (the variable region of the Fab) from molecule to molecule. Thus, the IgE molecules generally have identical "tail" peptide sequences but may have a great number of different "head" peptide sequences.
The allergic or immunologic release of histamine within the organism from the specialized mast cells and basophils can occur only under the following circumstances:
All mast cells or basophils possess a number of receptor sites that are available for "locking" onto the constant region or Fc portion of IgE molecules. These "binding sites" are specialized areas on the cell membranes wherein a special geometric or spatial molecular arrangement of molecules occurs, thus enabling this "binding or receptor site" to "lock" into the Fc fragment or a site in the constant region of the IgE molecule.
Should a wandering IgE molecule find a free "binding receptor site" on a mast cell or basophil, it locks or attaches at its Fc end onto the cell binding (receptor) site to secure the IgE molecule to the mast cell or basophil.
When the Fc portion of the IgE molecule is secured to the receptor "binding site", the upper arms of the "Y" shaped molecule (the F(ab) portion) are free to extend above the cell surface. These extended upper peptide chains in turn act as receptors to allergens which may be present in the organism's environment. If the polypeptide structure of the Fab portions are compatible with a particular allergen the allergen may attach to the outwardly extending Fab of the IgE polypeptide chain. Should such an attachment occur, the mast cell or basophil is automatically stimulated or "triggered" to release histamine from within its cell structure into the local environment of the mast cell or basophil. Once the histamine is released, the familiar "allergic symptoms" are manifested.
The present state of therapy of allergic disease includes hyposensitization (repeated injections of offending allergens to produce "blocking antibodies"), systemic therapy with anti-histamines (which compete with histamines released during the allergic reaction) and disodium cromoglycate (which may lower the amount of histamine released by allergic reactions). Corticosteroids, isoprenaline and theophylline as well as other medications are also utilized in the therapy of allergy. However, none of these aforementioned drugs or techniques interfere with the basic IgE-mast cell (basophil) reaction itself, and all have significant limitations in usefulness.
Another course of therapy suggested by the analysis above of the allergen-IgE-mast cell (basophil) reaction would be the introduction into the organism of a drug that would "block" the mast cell (basophil) receptor or binding sites against the attachment of the IgE molecule. Of equal importance would be a drug that would not only "block" the binding sites, but in addition would displace IgE from binding sites to which the IgE was already attached. Any filling up or diminution in the binding sites available for IgE attachment would quite obviously reduce the number of allergen-IgE-mast cell (basophil) reactions, and as a consequence, thereby reduce the release of histamine into the organism and thereby reduce or prevent the allergic reaction.
Some prior attempts have been made to use this therapeutic approach. For instance, in 1968 Stanworth, et al published in Lancet (July 6, 1968) a study wherein the whole Fc portion of the IgE as well as small proteolytic digestion fragments thereof were tested for their ability to suppress the allergic reaction. This study suggested that only the complete Fc fragment of IgE was as effective as the intact IgE Molecule in inhibiting allergic reaction while the digestion fragments were ineffective. That is, any fraction of the Fc peptide chain less than the entire Fc polypeptide was unable to prevent an induced allergic reaction. The Fc fragment itself cannot be used as a therapeutic agent or drug.